Affinage

SIRT3

NAD-dependent protein deacetylase sirtuin-3, mitochondrial · UniProt Q9NTG7

Length
399 aa
Mass
43.6 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIRT3 is an NAD+-dependent mitochondrial matrix deacylase that functions as a metabolic and redox sensor, coupling nutrient status to the acetylation state of the mitochondrial proteome (PMID:20203611, PMID:22114326). Its expression is driven transcriptionally by NRF-2 binding to the SIRT3 promoter (PMID:26109058) and upregulated during fasting (PMID:20203611, PMID:22114326), while its activity depends on mitochondrial NAD+ supplied through the transporter SLC25A51 (PMID:35932995). SIRT3 deacetylates a broad set of mitochondrial substrates to govern distinct programs: LCAD at K42 to sustain fatty-acid oxidation (PMID:20203611), the antioxidant enzyme SOD2 to limit superoxide and preserve endothelial function (PMID:28684630, PMID:31852393), ALDH2 to modulate xenobiotic toxicity (PMID:21720390), frataxin at K189 to support iron-sulfur cluster synthesis and macrophage efferocytosis (PMID:37646156), LONP1 at K145 to direct its ubiquitin-dependent degradation and restrain tumor growth (PMID:36739437), TFAM at K5/K7/K8 (PMID:38547618), and PINK1 to promote mitophagy, including via a SIRT3–PINK1–PKM2 axis (PMID:37417912, PMID:40087281). SIRT3 activity is tuned by multiple post-translational modifications: SUMOylation suppresses it and SENP1-mediated deSUMOylation activates it during fasting and AMPK signaling (PMID:31302001, PMID:37608549), CDK1-mediated phosphorylation at T150/S159 enhances it (PMID:26141949), S-glutathionylation inactivates it under oxidative stress (PMID:28684630), and S-sulfhydration of its zinc-finger CXXC sites stimulates it (PMID:37146925). Beyond the matrix, SIRT3 accumulates in the nucleus under stress to deacetylate PARP-1 (PMID:32139662) and p53 at K320 (PMID:37348684), and interacts with nuclear-envelope and heterochromatin proteins to stabilize lamina-associated domains and prevent senescence (PMID:33706382). SIRT3 additionally acts as a delactylase, removing lactyl groups from histone H4K16 and from non-histone proteins such as cyclin E2 at K348 to suppress hepatocellular carcinoma growth (PMID:36896611, PMID:37720100). Through these activities SIRT3 broadly protects against oxidative stress, fibrosis, cardiac dysfunction, and inflammation while exerting context-dependent roles in tumor metabolism (PMID:31185214, PMID:27815257, PMID:29915029, PMID:35418250).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2010 High

    Established SIRT3 as a fasting-induced mitochondrial deacetylase that directly controls a metabolic enzyme, defining its role as a nutrient-responsive regulator of fatty-acid oxidation.

    Evidence MS of mitochondrial proteins, in vitro deacetylation, and SIRT3-KO mice with metabolic phenotyping; subcellular fractionation in fasted vs fed mice

    PMID:20203611 PMID:22114326

    Open questions at the time
    • Did not establish the full substrate repertoire
    • Mechanism linking fasting signals to SIRT3 activation not defined
  2. 2010 High

    Resolved the isoform structure and mitochondrial processing of SIRT3, showing multiple transcripts yield catalytically active deacetylase forms.

    Evidence Transient transfection, mitochondrial targeting assays, Edman degradation, and deacetylase activity assays in murine SIRT3

    PMID:20677216

    Open questions at the time
    • Human isoform usage and tissue distribution not addressed
    • Relative in vivo activity of isoforms unresolved
  3. 2011 High

    Extended SIRT3 substrate range to ALDH2 and linked its deacetylation to xenobiotic detoxification phenotypes.

    Evidence SIRT3-KO mice with acetaminophen hepatotoxicity assay and direct substrate identification

    PMID:21720390

    Open questions at the time
    • Specific ALDH2 acetylation site not mapped
    • Direction of net protection context-dependent
  4. 2015 High

    Identified post-translational activation of SIRT3 by CDK1 phosphorylation, connecting cell-cycle/DNA-damage signaling to mitochondrial deacetylase activity and radioresistance.

    Evidence Site-directed mutagenesis (T150A/S159A), phosphorylation assays, clonogenic and xenograft assays

    PMID:26141949

    Open questions at the time
    • Whether phosphorylation alters substrate selectivity unknown
    • Structural basis of activation not defined
  5. 2015 Medium

    Showed transcriptional control of SIRT3 by NRF-2, placing SIRT3 expression downstream of a mitochondrial biogenesis transcription factor.

    Evidence Promoter bioinformatics, ChIP, siRNA knockdown and overexpression in cell lines

    PMID:26109058

    Open questions at the time
    • Single lab
    • Physiological contexts where NRF-2 dominates SIRT3 regulation not defined
  6. 2017 High

    Defined redox inactivation of SIRT3 by S-glutathionylation, mechanistically linking oxidative stress to SOD2 hyperacetylation and hypertension.

    Evidence SIRT3-KO mice, S-glutathionylation assays, SOD2 acetylation measurement, mitochondria-targeted antioxidant, human samples

    PMID:28684630

    Open questions at the time
    • Cysteine residue(s) of glutathionylation not pinpointed in this report
    • Reversal enzymology not characterized
  7. 2019 High

    Established SUMOylation as a reversible off-switch for SIRT3 and SENP1 as the fasting-activated deSUMOylase, defining a signaling route controlling fat metabolism.

    Evidence SUMOylation assays, SENP1 manipulation, mitochondrial fractionation, SUMO-deficient Sirt3 knock-in and HFD mouse models

    PMID:31302001

    Open questions at the time
    • SUMO acceptor lysine context and SUMO ligase not fully defined
    • How SENP1 enters mitochondria mechanistically unresolved
  8. 2019 High

    Demonstrated cell-type-specific metabolic roles: endothelial SIRT3 supports glycolysis/angiogenesis via PFKFB3, and SIRT3 sustains glutamine flux to fuel lymphoma growth.

    Evidence Endothelial-specific and lymphoma SIRT3 KO mice, Seahorse and metabolic flux analysis, GDH activity, pharmacological inhibitor

    PMID:28935506 PMID:31185214

    Open questions at the time
    • Tissue-specific substrate basis for opposing phenotypes not fully mapped
    • Mechanism of glycolytic regulation in endothelium incompletely defined
  9. 2021 Medium

    Revealed a nuclear/chromatin role for SIRT3 in maintaining lamina-associated domain attachment and preventing senescence, expanding its function beyond the matrix.

    Evidence CRISPR SIRT3 deletion in hMSCs, Co-IP with nuclear/heterochromatin proteins, ATAC-seq, RNA-seq, rescue

    PMID:33706382

    Open questions at the time
    • Direct chromatin substrate(s) not identified
    • How matrix-targeted SIRT3 reaches the nucleus unresolved
  10. 2022 Medium

    Connected mitochondrial NAD+ import to SIRT3 catalytic competence, showing SLC25A51 is required to maintain SIRT3 substrate deacetylation.

    Evidence shRNA knockdown of Slc25a51, mitochondrial NAD+ measurement, substrate acetylation Western blots, Seahorse, mouse liver knockdown

    PMID:35932995

    Open questions at the time
    • Single lab
    • Quantitative relationship between NAD+ levels and SIRT3 output not defined
  11. 2022 High

    Confirmed deacetylase activity is necessary for SIRT3 cardioprotection and that additional PTMs (S-sulfhydration) and metabolic substrates (SDH) integrate SIRT3 into redox, inflammation, and bone biology.

    Evidence M1/M3-SIRT3 transgenic mice with deacetylase-dead mutants, cardiac acetylome MS; CXXC-site mutagenesis; macrophage-specific KO with succinate/KLF4 readouts

    PMID:35418250 PMID:36894333 PMID:37146925

    Open questions at the time
    • Substrates mediating each phenotype not all mapped
    • Interplay between distinct activating PTMs unresolved
  12. 2023 High

    Identified SIRT3 as a delactylase acting on histone H4K16la and non-histone cyclin E2 K348la, defining a tumor-suppressive epigenetic/metabolic function with structural mechanism.

    Evidence SILAC proteomics, crystal structures with lactyl-lysine peptides, in vitro delactylation assays, HCC xenografts, chemical-probe pull-down

    PMID:36896611 PMID:37720100

    Open questions at the time
    • Full delactylation substrate landscape unknown
    • Relative physiological weight of deacetylase vs delactylase activity unresolved
  13. 2023 High

    Mapped specific deacetylation sites linking SIRT3 to iron-sulfur cluster synthesis (FXN K189) and oncogene turnover (LONP1 K145 via ESCRT/ubiquitination), with site-specific knock-in/mutant validation.

    Evidence Acetylome MS, FXN-K189R and LONP1 K145Q/K145R mutants, myeloid and intestinal Sirt3 KO mice, efferocytosis and ubiquitination assays

    PMID:36739437 PMID:37646156

    Open questions at the time
    • How a single deacetylase coordinates these divergent programs unclear
    • Tissue-specific substrate prioritization not defined
  14. 2024 High

    Defined a SIRT3–PINK1–PKM2 mitophagy/metabolic axis with direct deacetylation and downstream phosphorylation events, validated genetically.

    Evidence Direct deacetylation and phosphorylation assays, conditional and double-KO mice in an osteoarthritis model

    PMID:40087281

    Open questions at the time
    • PINK1 acetylation site(s) not mapped
    • Generality of the axis across tissues untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIRT3 substrate selection is partitioned across compartments (matrix deacetylation, nuclear deacetylation, and delactylation) and how its many activating/inhibiting PTMs are integrated in vivo remains unresolved.
  • No unified model for compartment-specific targeting
  • Quantitative hierarchy among PTM inputs unknown
  • Determinants of deacetylase vs delactylase preference undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 4 GO:0042393 histone binding 2
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 3 GO:0005635 nuclear envelope 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-4839726 Chromatin organization 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
CCNE2CDK1LRPPRCPARP-1PINK1SENP1SLC25A51TFAM

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 SIRT3 directly deacetylates long-chain acyl-CoA dehydrogenase (LCAD) at lysine 42 in vitro and in vivo; hyperacetylation of LCAD reduces its enzymatic activity, and SIRT3-knockout mice show impaired fatty-acid oxidation during fasting. Mass spectrometry of mitochondrial proteins, in vitro deacetylation assay, SIRT3-KO mouse model with metabolic phenotyping Nature High 20203611
2010 SIRT3 is localized to the mitochondrial matrix and its expression is upregulated during fasting in liver and brown adipose tissue, consistent with a role as a metabolic sensor. Subcellular fractionation, tissue expression analysis in fasted vs. fed mice Nature High 20203611 22114326
2011 SIRT3 directly deacetylates mitochondrial aldehyde dehydrogenase 2 (ALDH2); deacetylation increases acetaminophen toxic-metabolite binding to ALDH2, and SIRT3-KO mice are protected from acetaminophen hepatotoxicity. SIRT3-KO mouse model, direct substrate identification, in vivo hepatotoxicity assay EMBO reports High 21720390
2010 Murine SIRT3 produces three protein isoforms (M1, M2, M3) from alternative transcripts; the longer M1 and M2 isoforms are targeted to mitochondria and processed to a mature form, while all three isoforms show deacetylase activity toward full-length protein substrates. The N-terminal amino acid of the mature M1 isoform was identified as Ile38 (majority) or Val42 by Edman degradation. Transient transfection, mitochondrial targeting assays, Edman degradation, deacetylase activity assays with acetylated peptide and protein substrates Journal of cellular biochemistry High 20677216
2019 SIRT3 is SUMOylated in mitochondria; SUMOylation suppresses its catalytic deacetylase activity. During fasting, SENP1 translocates into mitochondria and deSUMOylates SIRT3, activating it and increasing fatty acid oxidation. SUMOylation-deficient Sirt3 mice show reduced fat mass and resistance to high-fat diet-induced obesity. SUMOylation assays, SENP1 knockdown/overexpression, mitochondrial fractionation, in vivo mouse models (fasting and HFD), mutant Sirt3 knock-in Molecular cell High 31302001
2017 SIRT3 depletion increases SOD2 acetylation, elevating mitochondrial superoxide and reducing endothelial nitric oxide. Angiotensin II-induced hypertension is associated with SIRT3 S-glutathionylation (redox inactivation) and consequent SOD2 hyperacetylation/inactivation. Mitochondria-targeted H2O2 scavenging prevented SIRT3 S-glutathionylation and reduced blood pressure in wild-type but not SIRT3-KO mice. SIRT3-KO mouse model, S-glutathionylation assays, SOD2 acetylation measurement, mitochondria-targeted antioxidant treatment, human hypertensive subject samples Circulation research High 28684630
2019 SIRT3 deficiency in Sirt3-KO mice causes SOD2 hyperacetylation, vascular oxidative stress, endothelial dysfunction, vascular hypertrophy, NF-κB activation, vascular inflammation, and age-dependent hypertension. Transgenic SIRT3 overexpression prevents these effects and attenuates angiotensin II- and DOCA-salt-induced hypertension. Global SIRT3-KO and SIRT3-overexpressing transgenic mice, vascular function assays, SOD2 acetylation quantification, human mediastinal arteriole samples Circulation research High 31852393
2015 SIRT3 enzymatic activity is enhanced by CDK1 (cyclin B1-CDK1)-mediated phosphorylation at Thr150/Ser159. Radiation induces CDK1 and SIRT3, and CDK1 relocalizes to mitochondria with SIRT3. Thr150Ala/Ser159Ala-mutant SIRT3 shows reduced mitochondrial protein deacetylation, reduced MnSOD activity, reduced ATP generation, and decreased clonogenicity and radioresistance. Site-directed mutagenesis, phosphorylation assays, mitochondrial fractionation, clonogenic survival assay, xenograft tumor model Molecular cancer therapeutics High 26141949
2023 SIRT3 functions as a delactylase that removes the lactyl moiety from lysine residues on non-histone proteins. Cyclin E2 (CCNE2) is identified as a SIRT3 delactylation substrate at K348; lactylated CCNE2 promotes HCC cell growth. Crystal structures of SIRT3 with lactyl-lysine peptides elucidate the mechanism of CCNE2 K348la delactylation. SILAC-based quantitative proteomics, crystallography, in vitro delactylation assay, in vivo HCC xenograft model EMBO reports High 36896611
2023 SIRT3 exhibits delactylase activity toward the histone H4K16la site with higher activity than other human sirtuins. Crystal structures reveal the binding mechanism of lactyl-lysine peptides with SIRT3. A chemical probe (p-H4K16laAlk) pulled down SIRT3 from cell lysates, confirmed by proteomics. Biochemical delactylase assay, crystal structure determination, chemical probe pull-down with proteomic validation, fluorescent probe for real-time activity detection iScience High 37720100
2019 SIRT3 depletion in endothelial cells causes a shift toward higher mitochondrial respiration and ROS formation, reduces glycolytic enzyme PFKFB3 expression, and impairs glycolysis and angiogenesis. Endothelial-specific SIRT3 KO mice develop myocardial capillary rarefaction, reduced coronary flow reserve, perivascular fibrosis, and diastolic dysfunction. Endothelial-specific SIRT3 KO mice, Seahorse metabolic analysis, angiogenesis assays, echocardiography, histology Journal of molecular and cellular cardiology High 28935506
2019 SIRT3 depletion impairs glutamine flux to the TCA cycle via glutamate dehydrogenase (GDH) and reduces acetyl-CoA pools, inducing autophagy and cell death in diffuse large B-cell lymphoma (DLBCL). SIRT3 KO attenuated B-cell lymphomagenesis in VavP-Bcl2 mice without affecting normal germinal center formation. SIRT3 KO mouse lymphoma model, metabolic flux analysis, GDH activity assay, pharmacological SIRT3 inhibitor (YC8-02) Cancer cell High 31185214
2016 SIRT3 overexpression in lung fibroblasts reverses TGF-β1-induced ROS production, mitochondrial DNA damage, and myofibroblast differentiation. SIRT3-KO mice show exacerbated bleomycin-induced pulmonary fibrosis with decreased OGG1 and increased 8-oxo-dG. SIRT3-overexpressing transgenic mice are protected from bleomycin-induced mtDNA damage and lung fibrosis. Adenovirus-mediated SIRT3 overexpression, SIRT3-KO mice, bleomycin lung fibrosis model, SIRT3 transgenic mice, mtDNA damage quantification American journal of physiology. Lung cellular and molecular physiology High 27815257
2015 Nuclear respiratory factor 2 (NRF-2) directly binds to the SIRT3 promoter and modulates SIRT3 transcript levels; NRF-2 knockdown or overexpression correspondingly reduces or increases SIRT3 expression. Bioinformatic promoter analysis, ChIP (NRF-2α binding to SIRT3 promoter), siRNA knockdown, overexpression in cell lines Aging cell Medium 26109058
2018 SIRT3 expression is downregulated during cell migration; SIRT3 controls ROS levels to repress Src oxidation and attenuate FAK activation, thereby inhibiting cell migration and metastasis. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells. Live cell imaging of mitochondria at leading edge, SIRT3 KD/OE, Src oxidation assay, FAK phosphorylation measurement, in vivo metastasis model Proceedings of the National Academy of Sciences of the United States of America High 29915029
2017 SIRT3 deacetylates and activates citrate synthase (CS); MPP+-induced decrease in SIRT3 expression is associated with increased CS acetylation and reduced CS enzymatic activity, which is partially rescued by SIRT3 overexpression. SIRT3 overexpression in SH-SY5Y cells, CS activity assay, protein acetylation measurement Biochemical and biophysical research communications Medium 28161643
2015 SIRT3 deacetylates lactate dehydrogenase A (LDHA) and enhances its enzymatic activity in gastric cancer cells, promoting glycolysis. Co-immunoprecipitation, in vitro deacetylation assay, LDHA activity measurement, SIRT3 KD/OE in gastric cancer cell lines PloS one Medium 26121691
2020 SIRT3 inhibits cardiac hypertrophy by accumulating in the nucleus under stress, interacting with PARP-1 via co-immunoprecipitation, and decreasing PARP-1 acetylation and activity. Adenovirus-mediated SIRT3 overexpression, co-immunoprecipitation, acetylation assay, cardiomyocyte hypertrophy model Aging Medium 32139662
2022 Mitochondrial NAD+ transporter SLC25A51 is required for SIRT3 activity; knockdown of Slc25a51 in hepatocytes decreases mitochondrial NAD+ and SIRT3 activity, reflected by increased acetylation of SIRT3 targets IDH2 and ACADL, and impairs mitochondrial oxygen consumption. shRNA knockdown of Slc25a51, mitochondrial NAD+ measurement, SIRT3 substrate acetylation by Western blot, Seahorse oxygen consumption assay, mouse liver-specific knockdown Metabolism: clinical and experimental Medium 35932995
2021 SIRT3 interacts with nuclear envelope proteins and heterochromatin-associated proteins; SIRT3 deficiency in human mesenchymal stem cells leads to detachment of lamina-associated domains from the nuclear lamina, increased chromatin accessibility, aberrant repetitive sequence transcription, and accelerated senescence. Re-introduction of SIRT3 rescues these phenotypes. CRISPR/Cas9 SIRT3 deletion, Co-IP with nuclear/heterochromatin proteins, ATAC-seq, RNA-seq, senescence assays Nucleic acids research Medium 33706382
2023 SIRT3 deacetylates frataxin (FXN) at lysine 189; FXN hyperacetylation (K189) reduces iron-sulfur cluster synthesis and causes mitochondrial iron accumulation in cardiac macrophages, impairing efferocytosis and promoting cardiac inflammation. FXN K189R knock-in mice show improved macrophage efferocytosis and reduced cardiac fibrosis. Quantitative acetylome mass spectrometry, myeloid SIRT3 KO mice, FXN-K189R knock-in mice, iron-sulfur cluster assay, efferocytosis assay Circulation research High 37646156
2023 SIRT3 deacetylates PINK1, promoting mitophagy in liver fibrosis; SIRT3 also deacetylates NIPSNAP1. Simultaneous interference with PINK1 or NIPSNAP1 disrupts the ability of SIRT3 overexpression to improve mitophagy and attenuate ECM production in liver fibrosis models. Co-immunoprecipitation, acetylation assay, SIRT3 KO mice (CCl4 model), in vitro LX-2 cell overexpression/knockdown, mitophagy markers (LC3, p62, TOM20/LAMP1 colocalization) Journal of cellular physiology Medium 37417912
2023 SIRT3 deacetylates LONP1 at lysine 145 (K145); LONP1 K145 hyperacetylation (mimicked by K145Q mutant) enhances oxidative phosphorylation to accelerate tumor growth, whereas the K145R deacetylation mutant restricts tumorigenesis. SIRT3-mediated K145 deacetylation facilitates ESCRT0-mediated K63-ubiquitination and degradation of oncogene LONP1. Mass spectrometry (deacetylation site), conditional intestinal Sirt3 KO mice (ApcMin/+), K145Q/K145R mutants, Seahorse metabolic assay, ubiquitination assay Journal of translational medicine High 36739437
2023 SIRT3 deacetylates p53 at K320, reducing its transcriptional activity and protecting against PM2.5-induced pulmonary epithelial senescence and ferroptosis. PM2.5 decreases SIRT3 protein via the proteasome pathway by downregulating USP3. SIRT3 conditional KO mice (AT2 cell-specific), adenovirus-mediated SIRT3 overexpression, acetylation mapping by Western blot, RNA-seq/KEGG analysis, USP3 knockdown Free radical biology & medicine Medium 37348684
2024 SIRT3 directly deacetylates PINK1 to promote mitophagy; PINK1 subsequently phosphorylates PKM2 at Ser127 to preserve its active tetrameric form, preventing nuclear translocation and β-catenin interaction, resulting in a metabolic shift in chondrocytes. Double-KO mice confirm the SIRT3-PINK1-PKM2 axis in protecting joint integrity. Direct deacetylation assay (SIRT3→PINK1), phosphorylation assay (PINK1→PKM2 S127), conditional SIRT3/PINK1 KO and double-KO mice, OA model Bone research High 40087281
2022 SIRT3 deacetylates TFAM at K5, K7, and K8 (identified by immunoprecipitation and mass spectrometry); decreased SIRT3 leads to TFAM hyperacetylation, mitochondrial dysfunction, and vascular dementia pathology. Co-immunoprecipitation, mass spectrometry for acetylation sites, SIRT3 knockdown with 3-TYP inhibitor, in vivo BCCAO VaD rat model Phytomedicine Medium 38547618
2022 SIRT3 deficiency leads to hyperacetylation of succinate dehydrogenase, causing succinate accumulation that increases histone methylation on the Kruppel-like factor 4 (KLF4) promoter, suppressing KLF4 transcription and driving proinflammatory macrophage polarization in obesity. Macrophage-specific Sirt3 KO mice, succinate measurement, succinate dehydrogenase acetylation assay, KLF4 promoter histone methylation ChIP, HFD mouse model Obesity (Silver Spring, Md.) Medium 36894333
2024 SIRT3 binds to and deacetylates leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), modulating oxidative phosphorylation and oxidative stress; SIRT3-KO accelerates hPDLSC senescence while SIRT3 activation by honokiol delays senescence and promotes alveolar bone regeneration. Co-immunoprecipitation, SIRT3 KD/OE, in vitro senescence assays, in vivo DP mouse model with honokiol treatment Free radical biology & medicine Medium 39557134
2023 SIRT3 regulates SLC7A11 transcription through ATF4 in glioblastoma; SIRT3 inhibition leads to ferrous iron and ROS accumulation in mitochondria, triggering mitophagy and downregulating SLC7A11, sensitizing GBM cells to RSL3-induced ferroptosis. Forced SLC7A11 expression partially rescues viability upon SIRT3 knockdown. SIRT3 knockdown in GBM cells, RNA-seq, ATF4 pathway analysis, in vivo xenograft model, SLC7A11 rescue experiment Cell death & disease Medium 38395990
2022 Full-length SIRT3 (M1-SIRT3) expression in vivo prevents doxorubicin-induced cardiac dysfunction and remodeling. Deacetylase-deficient SIRT3 mutants are unable to prevent oxidative stress in cardiomyocytes, establishing that deacetylase activity is required for cardioprotection. Mass spectrometry identified 37 unique acetylation sites on cardiac mitochondrial proteins altered by doxorubicin. M1-SIRT3 and M3-SIRT3 transgenic mice, echocardiography, mass spectrometry of cardiac mitochondrial acetylome, deacetylase-deficient mutant adenoviruses in primary rat and human iPSC-derived cardiomyocytes Circulation. Heart failure High 35418250
2023 The periostin/NAP1L2/SIRT3 axis mediates BCAA catabolism impairment in diabetic cardiomyopathy: periostin upregulates NAP1L2, which recruits SIRT3 to deacetylate H3K27ac on the promoters of BCAA catabolism enzymes BCAT2 and PP2Cm, resulting in their transcriptional suppression. RNA sequencing, ChIP for H3K27ac on BCAT2/PP2Cm promoters, periostin-KO and overexpression mice, CF-cardiomyocyte co-culture Cellular & molecular biology letters Medium 37993768
2023 S-sulfhydration of SIRT3 at CXXC sites of its zinc finger motif (by H2S/NaHS) enhances its deacetylase activity; mutation of these CXXC sites abolishes the anti-senescence effect of S-sulfhydration. SIRT3 S-sulfhydration stabilizes heterochromatin (H3K9me3/Lamin B1 interaction) and prevents mitochondrial fragmentation in BMSCs. S-sulfhydration assay, SIRT3 CXXC-site mutagenesis, SIRT3 KO cells and mice, in vivo OVX osteoporosis model with NaHS-pretreated BMSC transplantation Pharmacological research Medium 37146925
2016 SIRT3 inhibits ovarian cancer metastasis and epithelial-to-mesenchymal transition (EMT) by downregulating Twist; an interaction between SIRT3 and Twist was detected by Co-IP. SIRT3 knockdown enhanced migration/invasion and liver metastasis in vivo, while overexpression suppressed them. Co-immunoprecipitation (SIRT3-Twist interaction), SIRT3 KD/OE in ovarian cancer cells, in vivo liver metastasis model, EMT marker analysis Biochemical and biophysical research communications Medium 27216459
2022 Sirt3 regulates osteocyte dendritic process formation and mechanosensing through the PKA/CREB signaling pathway, regulating E11/gp38 expression. Deletion of Sirt3 in osteocytes impairs dendritic processes and abolishes bone gain in response to exercise in vivo. Osteocyte-specific Sirt3 KO mice, exercise loading model, PKA/CREB pathway analysis, E11/gp38 expression, honokiol pharmacological activation Cell death and differentiation Medium 36153410
2022 AMPK activation promotes the SENP1-Sirt3 axis in renal proximal tubular cells, decreasing SUMOylation of Sirt3, reducing SOD2 acetylation and mitochondrial ROS, and protecting against acute kidney injury and subsequent fibrosis. Sirt3 SUMOylation-site mutant (KR) knock-in mice, metformin/AMPK pathway studies, AKI mouse models (FA and IRI), mitochondrial ROS measurement, metabolomics Molecular therapy High 37608549
2022 1,4-dihydropyridine-based compounds identified as potent Sirt3-specific activators bind to the Sirtuin catalytic core independent of NAD+ and acylated peptides, stimulating turnover of peptide and protein substrates, and activate Sirt3 in cellular systems to regulate apoptosis and electron transport chain activity. In vitro sirtuin activity assay, binding assays, cell-based apoptosis and ETC activity assays Journal of medicinal chemistry Medium 36228194

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 1398 20203611
2013 SIRT3 reverses aging-associated degeneration. Cell reports 345 23375372
2019 Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress. Circulation research 295 31852393
2017 Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circulation research 261 28684630
2016 Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging cell 251 27686535
2013 SirT3 regulates the mitochondrial unfolded protein response. Molecular and cellular biology 243 24324009
2021 Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis. Redox biology 227 33662874
2023 SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth. EMBO reports 212 36896611
2012 SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. The Biochemical journal 200 22533670
2014 Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell death & disease 196 24503539
2019 SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism. Molecular cell 191 31302001
2015 SIRT3 regulates progression and development of diseases of aging. Trends in endocrinology and metabolism: TEM 173 26138757
2011 SIRT3 and cancer: tumor promoter or suppressor? Biochimica et biophysica acta 165 21586315
2011 SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harbor symposia on quantitative biology 160 22114326
2019 SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity. Cell death and differentiation 151 31160717
2018 SIRT3: A New Regulator of Cardiovascular Diseases. Oxidative medicine and cellular longevity 149 29643974
2021 SIRT3 consolidates heterochromatin and counteracts senescence. Nucleic acids research 144 33706382
2018 Acetylation of Mitochondrial Proteins in the Heart: The Role of SIRT3. Frontiers in physiology 138 30131726
2019 SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions. Autophagy 131 30774023
2010 Mitochondrial SIRT3 and heart disease. Cardiovascular research 129 20685942
2023 Resveratrol reduces ROS-induced ferroptosis by activating SIRT3 and compensating the GSH/GPX4 pathway. Molecular medicine (Cambridge, Mass.) 125 37858064
2017 SIRT3: Oncogene and Tumor Suppressor in Cancer. Cancers 112 28704962
2018 Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease. Journal of cellular physiology 104 30132870
2019 Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Cancer cell 103 31185214
2017 Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction. Journal of molecular and cellular cardiology 103 28935506
2024 2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis. Signal transduction and targeted therapy 102 38744811
2023 Identification of SIRT3 as an eraser of H4K16la. iScience 93 37720100
2022 The Role of SIRT3 in Exercise and Aging. Cells 93 36010672
2017 SIRT3 and mitochondrial metabolism in neurodegenerative diseases. Neurochemistry international 92 28449871
2018 The novel relationship between Sirt3 and autophagy in myocardial ischemia-reperfusion. Journal of cellular physiology 91 30485429
2020 The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis. Cellular and molecular life sciences : CMLS 90 32468094
2011 Sirt3, mitochondrial ROS, ageing, and carcinogenesis. International journal of molecular sciences 89 22016654
2018 Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3. International journal of molecular sciences 88 30126181
2015 SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells. PloS one 86 26121691
2015 CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance. Molecular cancer therapeutics 85 26141949
2018 Mst1 inhibits Sirt3 expression and contributes to diabetic cardiomyopathy through inhibiting Parkin-dependent mitophagy. Biochimica et biophysica acta. Molecular basis of disease 83 29674007
2022 Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3. Circulation 82 35100024
2016 SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage. American journal of physiology. Lung cellular and molecular physiology 81 27815257
2013 SIRT3: as simple as it seems? Gerontology 80 24192814
2017 Mitochondrial SIRT3 and neurodegenerative brain disorders. Journal of chemical neuroanatomy 77 29129747
2017 Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochimica et biophysica acta. Molecular basis of disease 71 28760703
2018 Emerging role of SIRT3 in mitochondrial dysfunction and cardiovascular diseases. Free radical research 70 30458637
2011 SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity. EMBO reports 70 21720390
2023 S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis. Pharmacological research 69 37146925
2022 Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress. Circulation. Heart failure 68 35418250
2015 Nuclear respiratory factor 2 induces SIRT3 expression. Aging cell 68 26109058
2017 SIRT3 Enhances Mesenchymal Stem Cell Longevity and Differentiation. Oxidative medicine and cellular longevity 65 28717408
2014 SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer & metabolism 64 25332769
2024 Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11. Cell death & disease 62 38395990
2018 Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3. Proceedings of the National Academy of Sciences of the United States of America 62 29915029
2022 Sirt3 deficiency accelerates ovarian senescence without affecting spermatogenesis in aging mice. Free radical biology & medicine 60 36336229
2022 Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells. International journal of molecular sciences 60 36499074
2011 The role of SIRT3 in mitochondrial homeostasis and cardiac adaptation to hypertrophy and aging. Journal of molecular and cellular cardiology 60 22119802
2023 PM2.5 contributed to pulmonary epithelial senescence and ferroptosis by regulating USP3-SIRT3-P53 axis. Free radical biology & medicine 59 37348684
2017 SIRT3 deacetylated and increased citrate synthase activity in PD model. Biochemical and biophysical research communications 59 28161643
2023 AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury. Molecular therapy : the journal of the American Society of Gene Therapy 56 37608549
2021 SIRT3 as a potential therapeutic target for heart failure. Pharmacological research 54 33508434
2017 SirT3 and p53 Deacetylation in Aging and Cancer. Journal of cellular physiology 53 27791271
2016 Down-regulation of SIRT3 promotes ovarian carcinoma metastasis. Biochemical and biophysical research communications 52 27216459
2016 SIRT3 in Cardiac Physiology and Disease. Frontiers in cardiovascular medicine 50 27790619
2023 Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders. Drug discovery today 49 37028501
2023 SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin. Circulation research 44 37646156
2020 SIRT1/SIRT3 Modulates Redox Homeostasis during Ischemia/Reperfusion in the Aging Heart. Antioxidants (Basel, Switzerland) 43 32933202
2022 Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5. Journal of medicinal chemistry 39 36228194
2016 SIRT3 in cardiovascular diseases: Emerging roles and therapeutic implications. International journal of cardiology 39 27393852
2024 Hesperetin promotes diabetic wound healing by inhibiting ferroptosis through the activation of SIRT3. Phytotherapy research : PTR 38 38234096
2024 The role of SIRT3 in homeostasis and cellular health. Frontiers in cellular neuroscience 38 39157755
2022 SIRT3 attenuates doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome via autophagy. Biochemical pharmacology 38 36435202
2022 SIRT3 regulates mitochondrial biogenesis in aging-related diseases. Journal of biomedical research 37 36056557
2024 Context-dependent role of SIRT3 in cancer. Trends in pharmacological sciences 35 38242748
2015 Expression of SIRT1 and SIRT3 varies according to age in mice. Anatomy & cell biology 35 25806122
2010 Characterization of murine SIRT3 transcript variants and corresponding protein products. Journal of cellular biochemistry 34 20677216
2020 SIRT3 inhibits cardiac hypertrophy by regulating PARP-1 activity. Aging 32 32139662
2020 PGC-1α activates SIRT3 to modulate cell proliferation and glycolytic metabolism in breast cancer. Neoplasma 32 33231084
2016 Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma. Biochemical and biophysical research communications 32 27114304
2022 The Double-Edged Sword of SIRT3 in Cancer and Its Therapeutic Applications. Frontiers in pharmacology 31 35571098
2025 SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch. Bone research 30 40087281
2024 SIRT3: A potential therapeutic target for liver fibrosis. Pharmacology & therapeutics 30 38561088
2024 The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases. International journal of molecular sciences 29 39000044
2022 The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions. Metabolism: clinical and experimental 29 35932995
2020 Autophagy-Sirt3 axis decelerates hematopoietic aging. Aging cell 29 32951306
2024 SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging. Cellular and molecular life sciences : CMLS 27 38294557
2023 Gastrodin alleviates rat chondrocyte senescence and mitochondrial dysfunction through Sirt3. International immunopharmacology 27 36933487
2022 Sirt3 Pharmacologically Promotes Insulin Sensitivity through PI3/AKT/mTOR and Their Downstream Pathway in Adipocytes. International journal of molecular sciences 27 35409099
2024 Gastrodin alleviates mitochondrial dysfunction by regulating SIRT3-mediated TFAM acetylation in vascular dementia. Phytomedicine : international journal of phytotherapy and phytopharmacology 26 38547618
2022 The Role of SIRT3 in the Osteoporosis. Frontiers in endocrinology 26 35692409
2022 Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation. European journal of pharmacology 26 35981603
2023 SIRT3 ameliorates polycystic ovary syndrome through FOXO1/PGC-1α signaling pathway. Endocrine 25 36598711
2023 SIRT3 regulates mitophagy in liver fibrosis through deacetylation of PINK1/NIPSNAP1. Journal of cellular physiology 25 37417912
2020 SIRT3 increases cisplatin sensitivity of small-cell lung cancer through apoptosis. Gene 25 32229158
2019 Probucol ameliorates EMT and lung fibrosis through restoration of SIRT3 expression. Pulmonary pharmacology & therapeutics 25 31085231
2023 Sirt3 restricts tumor initiation via promoting LONP1 deacetylation and K63 ubiquitination. Journal of translational medicine 24 36739437
2023 SIRT3 Activator Honokiol Inhibits Th17 Cell Differentiation and Alleviates Colitis. Inflammatory bowel diseases 24 37335900
2023 Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis. Cellular & molecular biology letters 24 37993768
2020 Effects of Sirt3‑autophagy and resveratrol activation on myocardial hypertrophy and energy metabolism. Molecular medicine reports 24 32468001
2024 Semaglutide protects against diabetes-associated cardiac inflammation via Sirt3-dependent RKIP pathway. British journal of pharmacology 23 39710830
2023 Mitochondrial dysfunction caused by SIRT3 inhibition drives proinflammatory macrophage polarization in obesity. Obesity (Silver Spring, Md.) 23 36894333
2022 Mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension. Current opinion in nephrology and hypertension 23 35086984
2022 Sirt3 mediates the benefits of exercise on bone in aged mice. Cell death and differentiation 23 36153410
2024 SIRT3 alleviates mitochondrial dysfunction and senescence in diabetes-associated periodontitis by deacetylating LRPPRC. Free radical biology & medicine 21 39557134

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